Miscellaneous Tumors

Incidence and Risk Factors

Hemangiosarcoma (HSA), also known as malignant hemangioendothelioma or angiosarcoma, is a malignant neoplasm of vascular endothelial origin. HSA occurs more frequently in dogs than in any other species.^1,2 It represents about 5% of all noncutaneous primary malignant neoplasms and 12% to 21% of all mesenchymal neoplasms in the dog.^3-5 HSA accounts for 2.3% to 3.6% of skin tumors in dogs^1,6 and 45% to 51% of splenic malignancies.^2,7,8 It is less common in the cat, occurring in approximately 0.5% of cats examined at necropsy in one study and accounting for 2% of all neoplasms in another.^9,10

HSA is seen mostly in middle-aged to older animals, although there are reports in dogs less than 3 years of age.^7,10-14 German shepherds, golden retrievers, and Labrador retrievers are overrepresented in many case series.^7,11,14-16 There may be a slight male predisposition in dogs.^{11,12,14,15,17}

Although the etiology is unknown, reports in humans have been related to exposure to thorium dioxide, arsenicals, vinyl chloride, and androgens.¹⁸ It is reported as a rare late sequela to breast-conserving irradiation in humans with breast cancer.¹⁹ The human vascular neoplasm Kaposi’s sarcoma is causally associated with human herpesvirus 8, and although some studies have demonstrated herpesviral elements in human angiosarcoma as well, the majority have not.^20-23 There is a documented increase in HSA development in dogs exposed to ionizing radiation prenatally or postnatally.²⁴ Cutaneous HSAs are found more frequently in dogs with minimal pigmentation and thin hair coats²⁵ and have been associated with ultraviolet light exposure in laboratory dogs.²⁶

There is increasing evidence that dysregulation of molecular pathways governing angiogenesis may be important in the pathogenesis of HSA. Studies in humans and dogs have demonstrated abundant expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiopoietins-1 and -2 (Ang-1 and -2) in HSA cells and tissues and concomitant expression of the cellular receptors for VEGF, bFGF, and Ang-1.^27-36 This suggests the potential for autocrine stimulation of one or more of these receptors leading to dysregulated proliferation and survival. Indeed, enforced overexpression of VEGF is sufficient to transform immortalized murine endothelial cells into HSA,³⁷ and in vivo overexpression of VEGF has led to vascular tumor formation in mice.³⁸

Mutations in tumor suppressor genes such as p53,^39,40 Ras,^41-43 and Tsc2⁴⁴ have likewise been implicated in the pathogenesis of HSA, based on murine or human studies. Recent studies suggest that p53 and Ras mutations are infrequent in canine HSA^45-47; however, PTEN inactivation was demonstrated in greater than 50% of evaluated canine HSA samples in one study.⁴⁸ Key growth- and apoptosis-regulating proteins such as pRB, cyclin D1, BCL2, and survivin appear overexpressed in HSA when compared with hemangiomas or normal tissues.^46,49 Gene expression profiling studies indicate an enrichment for genes involved in inflammation and angiogenesis.⁴⁷

Pathology and Natural Behavior

In the dog, the most common primary site for HSA is the spleen.^{1,11,12,14,15} Other frequent sites include the right atrium, skin and subcutis, and liver.^{11,14,25,50-53} Occurrence has also been reported in the lung, kidney, oral cavity, muscle, bone, urinary bladder, left ventricle, uterus, tongue, digit, and retroperitoneum.^12,14,54-60 In the cat, cutaneous and visceral (e.g., spleen, liver, intestine) locations are evenly distributed.^10,61 Other reported sites in the cat include the heart, thoracic cavity, eyelid, and nasal cavity.^10,53,61-64 HSA is the most common splenic neoplasm encountered but is by no means the only differential for splenomegaly or splenic masses in dogs. The “double two-thirds rule” has been applied to canine splenic masses: approximately two-thirds of dogs with splenic masses will have a malignant tumor, and approximately two-thirds of those malignancies will be HSA^2,8,17,65; however, recent studies have found that 63% to 70% of dogs with splenic masses presenting with nontraumatic hemoabdomen were HSA.^66-68 Several splenic mass lesions (e.g., HSA, hematoma, hemangioma) can have a similar gross and ultrasonographic appearance, and large masses do not necessarily denote malignancy.⁶⁹ Histopathology is necessary to establish a definitive diagnosis in these cases.

HSA may be solitary, multifocal within an organ, or widely disseminated at presentation. Grossly, they are of variable size, pale gray to dark red or purple, and soft or gelatinous, often containing blood-filled or necrotic areas on cut surface (Figure 33-1). They are poorly circumscribed, nonencapsulated, and often adhered to adjacent organs. They are extremely friable, and complications associated with rupture and hemorrhage are frequent presenting complaints. Histologically, HSA consists of immature, pleomorphic endothelial cells forming vascular spaces containing variable amounts of blood and/or thrombi.^70,71 When such features are minimal but HSA is suspected, immunohistochemistry for von Willebrand’s factor (factor VIII–related antigen) or CD31/platelet endothelial cell-adhesion molecule (PECAM) can be used to demonstrate endothelial derivation and support the diagnosis of HSA.^71-74 Recently, claudin-5 and CD117 (KIT) have also been identified as potentially useful immunohistochemical markers for distinguishing canine tumors of vascular endothelial origin.^75,76

Perhaps owing to its intimate association with the vasculature, facilitating extravasation and angiogenesis of metastatic clones, canine HSA is typified by very aggressive biologic behavior, with rapid and wide metastasis occurring frequently. An exception to this rule is pure cutaneous or dermal HSA, without any clinical or histologic evidence of subdermal infiltration.⁵¹ Metastasis is typically hematogenous or through transabdominal implantation following rupture. The most frequent metastatic sites are the liver, omentum, mesentery, and lungs.^14,77 One study suggested that approximately, 25% of dogs with splenic HSA will also have right atrial involvement.⁷⁷ However, the experience of the author suggests that this percentage at initial presentation is significantly lower (5% or less). Other reported sites of metastasis are the kidney, muscle, peritoneum, lymph nodes, adrenal gland, brain, and diaphragm. In dogs, HSA is considered the most common metastatic tumor to the brain.^78,79

HSA in cats is considered to be a less aggressive disease. Cutaneous or subcutaneous HSA often behaves in a fashion similar to other soft tissue sarcomas, and local recurrence is the major concern.^72,80,81 Reports do exist of more aggressive biologic behavior in a subset of cats with cutaneous HSA, however.^80-82 Visceral HSAs have a higher metastatic rate, similar to that in dogs, and the common sites include the liver, omentum, diaphragm, pancreas, and lung.^{10,61,81,83,84}

History and Clinical Signs

Presenting complaints vary, depending on the location of the primary tumor, and can range from vague, nonspecific signs of illness, to asymptomatic abdominal swelling, to acute collapse and death secondary to hemorrhagic/hypotensive shock. Common presenting complaints for visceral HSA are acute weakness or collapse. This may have been preceded by similar transient episodes occurring over a period of weeks or days, which resolved spontaneously in 12 to 36 hours. In such cases, it is theorized that HSA rupture leads to hemoperitoneum, followed by subsequent reabsorption (i.e., autotransfusion) of red blood cells. For those dogs that present asymptomatically or with vague signs (lethargy, inappetence, weight loss, abdominal distension), an abdominal mass may be palpated during examination. Dogs with cardiac HSA typically present with signs related to pericardial tamponade and associated right-sided heart failure, such as exercise intolerance, dyspnea, and ascites.

Common physical examination findings for visceral HSA include pale mucous membranes with delayed capillary refill, tachycardia with poor pulse quality, and a palpable fluid wave in the abdomen, with or without a palpable abdominal mass. Dogs with cardiac HSA may display ascites, muffled heart sounds, and/or pulsus paradoxus (variation in pulse quality associated with respiration).

In the cat, signs will depend on location and extent of tumor. Cats with visceral tumors usually have a history of lethargy, anorexia, vomiting, sudden collapse, dyspnea, or a distended abdomen.^61,81,83 On physical examination, pallor, pleural or peritoneal fluid, and a palpable abdominal mass may be detected.

Diagnostic Techniques and Work-Up

Complete staging for an HSA suspect typically includes hematology and serum biochemistry, coagulation testing, thoracoabdominal imaging, ±abdominocentesis, and/or echocardiography.

In both dogs and cats, anemia is often seen, usually characterized by the presence of schistocytes (associated with microangiopathic hemolysis) and acanthocytes in the peripheral blood.* Anemia may be regenerative or nonregenerative, depending on duration. Blood typing and/or crossmatching may be indicated if surgery is planned in a severely anemic patient. In addition, a neutrophilic leukocytosis may be seen.^61,66 Thrombocytopenia is observed in 75% to 97% of cases, ranging from mild to severe.^66,67,86,87 Serum biochemistry changes are typically nonspecific and can include hypoalbuminemia, hypoglobulinemia, and mild elevations in liver enzymes.^66,83

A coagulogram is very useful in animals with suspected HSA. Perturbations in some aspect of the coagulation cascade (prothrombin time [PT], activated partial thromboplastin time [APTT], platelet count, activated clotting time, fibrinogen concentration, fibrin degradation products) are seen in the majority of patients (Table 33-1)^66,86-91 and approximately 50% have coagulation abnormalities that meet the criteria for disseminated intravascular coagulation (DIC).^86,88 Tumor vasculature, especially in the case of HSA, differs significantly from normal vasculature, commonly containing blind-ended or irregular tortuous vessels, incomplete endothelial lining, arteriovenous shunts, exposed subendothelial collagen, and platelet-tumor aggregates.⁹² HSA-derived endothelial cells may also have an “activated” phenotype, further promoting initiation of the coagulation cascade.

HSA effusions are serosanguineous (or frank blood) and usually do not clot. Cytology of effusions is rarely diagnostic; although tumor cells are likely present, they are heavily diluted with peripheral blood.

Screening for metastasis is mandatory prior to definitive surgery for HSA. Dogs with gross evidence of metastasis have a grave prognosis, and surgery is purely palliative. Thoracic radiographs should be obtained in all cases. One study reported a 78% sensitivity and 74% negative predictive value for detecting pulmonary manifestations of HSA, and obtaining three views significantly decreased the false-negative rate.⁹³ Dogs with hemopericardium secondary to cardiac HSA will typically have a globoid cardiac silhouette, with or without distension of the caudal vena cava.⁹⁴ Abdominal radiographs may reveal a cranial abdominal mass in many cases; however, abdominal ultrasound is a superior modality for imaging the abdomen. Many animals with visceral HSA will have ascites, which diminishes abdominal detail with radiographs but not ultrasound. Ultrasound also allows for the more thorough evaluation of the rest of the abdomen for evidence of metastatic disease. HSA typically has a heteroechoic appearance, ranging from anechoic/cavitated to hyperechoic, or a targetoid appearance (Figure 33-2).^95,96

Typical electrocardiographic signs consistent with pericardial effusion (decreased amplitude QRS complex, electrical alternans) can be seen in dogs with cardiac HSA and hemopericardium. Echocardiography can be useful in dogs with suspected pericardial effusion, and a right atrial mass may be visible in 65% to 90% of cases (Figure 33-3)^97-100; however, some dogs may develop blood clots within the pericardium that can have a mass effect. Thus the absence of a mass does not rule out HSA, and the presence of a mass is not pathognomonic. Despite this, detection of a mass on echocardiography is strongly associated with a worse prognosis in dogs with pericardial effusion.^94,99 Other negative prognostic factors include history of collapse and presence of ascites.⁹⁴ Routine evaluation of the heart for metastatic disease in a dog with subcutaneous or visceral HSA without evidence of other metastasis is rarely rewarding.

A clinical staging system for HSA is given in Table 33-2.

Ultimately, a definitive diagnosis of HSA usually requires a surgical biopsy. Needle aspiration cytology of suspicious masses, although simple and cost-effective, is of low diagnostic utility due to the hemodilution that usually accompanies sampling.¹⁰¹ Needle core biopsies can be obtained of cutaneous or subcutaneous lesions but should not be performed on suspect visceral lesions due to the risk of induction of hemorrhage and subsequent seeding of the peritoneum. If only small samples of suspected HSA are submitted, histopathology may only reveal blood clots or other nonspecific findings. Submission of large samples of suspected HSA is preferred to maximize the likelihood of capturing a true tumor if present. This includes submission of entire spleens whenever possible or, at the very least, numerous parts of the mass.

Several investigators are evaluating additional tests, which may allow more accurate presurgical diagnosis. Pericardial fluid pH was suggested to correlate with presence or absence of neoplasia in one study¹⁰²; however, subsequent studies have shown pericardial fluid analysis to be of little diagnostic benefit.^103,104 Recent studies have found a significant difference in concentrations of troponin I, an indicator of myocardial damage, between dogs with cardiac HSA and dogs with idiopathic pericardial effusions.^105,106 Plasma concentrations of VEGF and urine concentrations of bFGF are elevated in dogs with HSA versus normal controls^27,28; however, neither was found to correlate with remission status, disease stage, or outcome. Advanced imaging techniques such as contrast-enhanced ultrasound,^107-113 contrast-enhanced computed tomography (CT),¹¹⁴ and magnetic resonance imaging (MRI)¹¹⁵ have been useful in discriminating malignant versus benign lesions in preliminary studies. Additional blood-based biomarkers showing early promise include measurement of serum alpha-1 acid glycoprotein,¹¹⁶ lipocalin region of collagen XXVII alpha 1,¹¹⁷ and thymidine kinase activity,^118,119 as well as multiparameter flow cytometry of peripheral blood utilizing a variety of endothelial and primitive hematopoietic cell markers.¹²⁰

Treatment

Prognosis

Comparative Aspects

In humans, a spectrum of endothelial tumors, including hemangioma, hemangioblastoma, Kaposi’s sarcoma, hemangioendothelioma, and angiosarcoma, is seen. Angiosarcoma is extremely rare in humans and can be a late sequela to RT in women treated for breast cancer.¹⁶⁷ With this exception, it has a lesion distribution and behavior similar to canine HSA. As in dogs, metastasis is frequent and adjuvant chemotherapy provides minimal benefit.

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Incidence and Risk Factors

Thymomas are one of the most common tumors of the cranial mediastinum, second only to lymphoma, yet they are uncommon in both dogs and cats. Thymomas can occur at any age but usually affect older patients. The reported peak age for presentation is 9 and 10 years in dogs and cats, respectively.^1,2 Breed predisposition has not been reported, and most studies do not show a sex predisposition.^1,2 Risk factors predisposing animals to thymoma have not been identified.

Pathology and Natural Behavior

Thymomas are neoplasms of thymic epithelial cells.¹ Different histologic types of thymoma have been described and include differentiated epithelial, lymphocyte-rich, and clear-cell type. The degree of lymphocyte infiltration within thymomas in dogs and cats has been shown to correlate positively with survival.^1,3 In cats, cystic thymomas seem to be the most common form, although squamous cell carcinoma variants and a thymolipoma have been reported.^1,4-8 The terms benign or malignant thymoma are commonly used and are based on clinical criteria of invasiveness and resectability rather than on histologic features of malignancy. Distant metastasis has been rarely reported in dogs.^5,9-11 The same is probably true in cats, although one study revealed a 20% metastatic rate in cystic thymomas in the species.⁶ The differential diagnoses for mediastinal masses should include lymphoma, ectopic thyroid tumor, branchial cysts, rare sarcomas, and metastatic neoplasms. Tumors extending from the ribs or sternum into the mediastinum may sometimes resemble a mediastinal mass.¹²

History and Clinical Signs

Clinical signs are usually related to organ displacement due to the presence of a mediastinal mass and include lethargy, coughing, tachypnea, and dyspnea. Less commonly, cranial vena cava syndrome (edema of the head, neck, and front limbs) may occur and is related to obstruction of vessels draining the cranial part of the body.^3-7,10-12 Paraneoplastic syndromes are common in dogs and cats and may occur in as many as 67% of dogs with thymoma.^3,4 Reported paraneoplastic syndromes include myasthenia gravis (MG), exfoliative dermatitis, erythema multiforme, hypercalcemia, T-cell lymphocytosis, anemia, and polymyositis. Myasthenia gravis may occur in up to 40% of dogs with thymoma and has also been reported in cats.^3,10,11 Concurrent megaesophagus and aspiration pneumonia has been reported in as many as 40% of canine patients.³ Paraneoplastic syndromes may occur at presentation, later in the course of the disease, or after tumor removal.*

Diagnostic Techniques and Work-Up

Physical examination findings may include edema of the head, cervical area, or front limbs, secondary to cranial vena cava syndrome. The jugular veins may be dilated and tortuous. Auscultation of the thoracic cavity may reveal decreased or absent lung sounds in the cranial mediastinum related to displacement by the mass or pleural effusion. Cardiac displacement may also occur, and the heart sounds may be heard either more dorsally, caudally, or both. In small dogs and cats, decreased compressibility of the anterior thorax may also be detected.^3-6,10-11,22

Complete blood count (CBC) is usually normal, but anemia, thrombocytopenia (secondary to immune-mediated destruction), and lymphocytosis may occur. Hypercalcemia, although uncommon, has been reported in association with thymomas but is much more common in cases of mediastinal lymphoma.^5,11,23 In both tumors, hypercalcemia is usually the result of excessive production of parathyroid hormone–related peptide (PTHrP). The presence of hypercalcemia in an animal with a mediastinal mass should not be used as the sole means to differentiate thymoma from lymphoma.^22-26

Thoracic radiographs may reveal the presence of a cranial mediastinal mass, pleural effusion, and cardiac displacement (Figure 33-4). Dilatation of the esophagus in the presence of megaesophagus secondary to MG and an increase in alveolar or interstitial lung pattern suggestive of aspiration pneumonia may also be detected. When MG is suspected, demonstration of serum antibodies against acetylcholine receptor is indicated. The Tensilon test (edrophonium chloride, which is an ultrashort anticholinesterase agent) can be used in cases suspected of having MG, in which muscle weakness and fatigue are observed. A marked short-lived improvement in muscle strength is considered a positive response.^18-21 In cases presenting with pleural effusion, fluid analysis after thoracocentesis usually reveals a modified transudate and numerous small mature lymphocytes or a mixed lymphocyte population.^3-5,10,22 Thoracic ultrasonography can be used to determine a presumptive diagnosis of thoracic masses, including thymomas. In addition ultrasound can guide biopsy needles for sampling of the mass.^27,28 More recently, endoscopic thoracic ultrasound has been described in dogs with the reported advantage of a decrease in artifacts caused by the lungs.²⁹ Transthoracic ultrasound-guided fine-needle aspiration (FNA) of the mediastinum can be easily and safely performed after deep sedation and analgesia or general anesthesia. The diagnosis of thymoma is made when the presence of neoplastic epithelial cells interspersed between large numbers of small mature lymphocytes (and occasional mast cells) is observed.^30,31 Unfortunately, nondiagnostic samples are common due to either a small percentage of epithelial cells, the presence of only small mature lymphocytes in the samples, or the presence of cysts within the mass. The diagnosis is further complicated due to the fact that both lymphoma and thymoma may be composed primarily of small lymphocytes. In three studies, a presumptive diagnosis of thymoma was achieved in approximately 20%, 40%, and 77% of mediastinal masses after FNA and cytology. In addition, Hassall’s corpuscles, cytoplasmic structures present in thymocytes, are not usually visualized in Wright-Giemsa preparations in comparison to hematoxylin-eosin (H&E) used for formalin-fixed samples.^3,10,30,31

Flow cytometry has been recently reported to aid in the specific diagnosis of mediastinal tumors. Flow cytometry of the thymus is based on the fact that thymic lymphocytes can be differentiated from peripheral lymphocytes by simultaneous expression of CD4 and CD8. In that study, all cases of thymoma expressed 10% lymphocytes co-expressing CD4 and CD8, whereas six of seven lymphomas contained less than 2% of CD4⁺CD8⁺ lymphocytes. The additional case of lymphoma was readily differentiated from thymoma by flow cytometric scatter plot analysis.³²

Advanced imaging modalities such as CT are now used to help the surgeon evaluate the possibility of resection. Three-dimensional (3D) CT reconstructions can estimate the size and volume of the mass, in addition to identifying neighboring structures and whether invasion of these structures has occurred. If the tumor is deemed inoperable, CT will still be helpful if radiotherapy is to be employed (Figure 33-5). Furthermore, CT-guided biopsies can be obtained during the process. Despite these advantages, nonangiographic CT has been shown to have limitations, which were outlined by a recent study. In that study, nonangiographic CT scanning significantly underestimated vascular invasion when compared to surgical exploration. These limitations can be potentially overcome by the use of CT angiography.^33-36

Therapy

A variety of different modalities have been described for the treatment of thymomas in dogs and cats, including surgery, RT, and chemotherapy and multimodality treatments. Unfortunately, there are no available studies comparing outcomes of animals treated with these different modalities. In addition, in many studies, animals were treated by a combination of different methods.* In a recent retrospective study that evaluated 11 dogs and 9 cats with invasive and noninvasive thymomas treated by surgery alone, the median survival was 790 days and 1825 days, respectively. The 1- and 3-year survival rates were 64% and 42% for dogs and 89% and 74% for cats, respectively.³ The successful resection of noninvasive thymomas in two dogs by video-assisted thoracoscopy has also been reported.³⁸

In another retrospective study, 17 dogs and 7 cats with thymoma were treated with RT alone or as an adjunctive therapy. Twenty cases were available for follow-up, and a response rate of 75% (11 partial responses [PRs]; 4 complete responses [CRs]) was observed. MSTs for dogs and cats were 248 days and 720 days, respectively. In that study, the total radiation dose (15 to 54 Gy) and treatment interval (from daily to once weekly) varied markedly among animals. To further confound the effects of RT in thymomas, the same study reported that many animals received concurrent chemotherapy.³⁷

The effects of chemotherapy for the treatment of thymomas have not been well evaluated in veterinary patients. Long-term remission and stable disease after treatment of thymomas in humans and dogs have been reported (single-case reports) with the use of high-dose prednisone. In one report a cat with thymoma achieved partial remission after treatment with DOX. Likely, the effects of chemotherapy and RT against thymomas reflect, at least in part, a greater reduction in the nonneoplastic lymphocyte population in the thymus, rather than in the primary carcinoma cells.^3-5,10,39

Prognosis

Surgically resectable thymomas in dogs without megaesophagus and aspiration pneumonia are thought to carry a good prognosis.^3,5,10 The definition of surgical resectability will depend on the experience and ability of the surgeon. Vascular invasion, which could potentially limit resection in the past, may be managed with a jugular vein autograft for reconstruction of the cranial vena cava in a dog with invasive thymoma.⁴⁰

As mentioned previously, thymomas with a significant lymphocytic infiltrate demonstrate improved survival. Age of the dog or cat, invasiveness of the tumor, and mitotic index had no effect on prognosis.³

In cats, cystic thymomas are commonly reported and they have been associated with better prognosis, although no other possible prognostic factors such as surgical resectability were critically evaluated.^3,41

In conclusion, long-term survival should be expected for dogs and cats with thymomas that can be completely resected. Vascular invasion may increase surgical complexity but not necessarily exclude surgery as an option.

Comparative Aspects

Thymic neoplasms in humans constitute 30% of anterior mediastinal masses in adults and less than 15% in children. The majority will occur in elderly patients, 60 years or older, and no sex or race predilection is thought to occur.^42,43 A clinicopathologic classification has been adopted by the World Health Organization (WHO) and correlates well with behavior. In the WHO system, cells are classified as spindle (predominant in the medullary), oval and epithelioid (predominant in the cortex), or dendritic. The tumors are then further divided into medullary, mixed, predominantly cortical and cortical thymomas, and well-differentiated and high-grade thymic carcinoma. Medullary and mixed thymomas are considered benign tumors even in the face of capsular invasion. Predominantly cortical and cortical thymomas display intermediate aggressiveness and have a low risk of relapse independent of their invasiveness. Well-differentiated and high-grade thymomas are considered to be highly invasive and are associated with a high frequency of relapse and death. A staging system that employs both surgical and histologic signs of invasiveness to describe five different stages correlates well with prognosis.^42,44

MG is the most common paraneoplastic syndrome associated with thymomas, occurring in 30% to 50% of patients. Red cell aplasia and hypogammaglobulinemia are reported to occur in 5% to 10% of patients.

Complete surgical resection is considered the best predictor for long-term survival for humans with thymomas and is the standard of care in patients with resectable tumors. RT is indicated most commonly for extensive or recurrent disease. A variety of chemotherapy drugs have been used to treat inoperable thymomas or in cases in which gross residual disease is present after surgery. Cisplatin, ifosfamide, and prednisone are considered the most effective agents. In addition neoadjuvant chemotherapy has been shown to influence long-term survival for thymomas of Masaoka stages III and IVa.⁴⁵

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21. Singh, A, Boston, SE, Poma, R. Thymoma-associated exfoliative dermatitis with post-thymectomy myasthenia gravis in a cat. Can Vet J. 2010;51:757–760.

22. Theilen, GH, Madewell, BR. Tumors of the respiratory tract and thorax. In: Veterinary cancer medicine. Philadelphia: Lea & Febiger; 1979.

23. Foley, P, Shaw, D, Runyon, C. Serum parathyroid hormone-related protein concentration in a dog with thymomas and persistent hypercalcemia. Can Vet J. 2000;41:867–870.

24. Harris, CL, Klausner, JS, Caywood, DD, et al. Hypercalcemia in a dog with thymomas. J Am Anim Hosp Assoc. 1991;27:281–284.

25. Bolliger, AP, Graham, PA, Richard, V, et al. Detection of parathyroid hormone-related protein in cats with humoral hypercalcemia of malignancy. Vet Clin Pathol. 2002;31:3–8.

26. Marconato, L, Stefanello, D, Valenti, P, et al. Predictors of long-term survival in dogs with high-grade multicentric lymphoma. J Am Vet Med Assoc. 2011;238:480–485.

27. Reickle, JK, Wisner, ER. Non-cardiac thoracic ultrasound in 75 feline and canine patients. Vet Radiol Ultrasound. 2000;41:154–162.

28. Larson, MM. Ultrasound of the thorax (non-cardiac). Vet Clin North Am. 2009;39:733–745.

29. Gashen, L, Kircher, P, Hoffman, G, et al. Endoscopic ultrasound for the diagnosis of intrathoracic lesions in two dogs. Vet Radiol Ultrasound. 2003;44:292–299.

30. Rae, CA, Jacobs, RM, Couto, CG. A comparison between the cytological and histological characteristics in thirteen canine and feline thymomas. Can Vet J. 1989;30:497–500.

31. Cowell, RL, Tyler, RD, Meinkoth, JH, The lung parenchyma. Diagnostic cytology of the dog and cat ed 2. St Louis: Mosby; 1999.

32. Lana, S, Plaza, S, Hampe, K, et al. Diagnosis of mediastinal masses in dogs by flow cytometry. J Vet Intern Med. 2006;20:1161–1165.

33. Yoon, J, Feeney, DA, Cronk, DE, et al. Computed tomographic evaluation of canine and feline mediastinal masses in 14 patients. Vet Radiol Ultrasound. 2004;45:524–526.

34. Zekas, LJ, Crawford, JT, O’Brien, RT. Computed tomographic-guided biopsy of intrathoracic lesions in 50 dogs and cats. Vet Radiol Ultrasound. 2005;46:200–204.

35. Hylands, R. Veterinary diagnostic imaging. Thymoma. Can Vet J. 2006;47:593–596.

36. Scherrer, W, Kyles, A, Samii, V, et al. Computed tomographic assessment of vascular invasion and resectability of mediastinal masses in dogs and cats. NZ Vet J. 2008;56:330–333.

37. Smith, AN, Wright, JC, Brawner, WR, Jr., et al. Radiation therapy in the treatment of canine and feline thymomas: a retrospective study (1985-1999). J Am Anim Hosp Assoc. 2001;37:489–496.

38. Mayhew, PD, Friedberg, JS. Video assisted thoracoscopic resection of noninvasive thymomas using one-lung ventilation in two dogs. Vet Surg. 2008;37:756–762.

39. Moore, AS. Chemotherapy for intrathoracic cancer in dogs and cats. Prob Vet Med. 1992;4:351–364.

40. Holsworth, IG, Kyles, AE, Bailiff, NL. Use of a jugular vein autograft for reconstruction of the vena cava in a dog with invasive thymoma and cranial vena cava syndrome. J Am Vet Med Assoc. 2004;225:1205–1210.

41. Gores, BR, Berg, J, Carpenter, JL. Surgical treatment of thymomas in cats: 12 cases (1987-1992). J Am Vet Med Assoc. 1994;204:1782–1785.

42. Tomaszek, S, Wigle, DA, Keshavjee, S, et al. Thymomas: review of current clinical practice. Ann Thorac Surg. 2009;87:1973–1980.

43. Masaoka, A, Monden, W, Nakahara, K, et al. Follow-up study of thymomas with special reference to their clinical stages. Cancer. 1981;48:2485–2492.

44. Ried, M, Guth, H, Potzger, T, et al. Surgical resection of thymomas still represents the first choice of treatment. Thorac Cardiovasc Surg. 2011;60(2):145–149.

45. Cardillo, G, Carleo, F, Giunti, R, et al. Predictors of survival in patients with locally advanced thymomas and thymic carcinoma (Masaoka stages III and IVa). Eur J Cardiothorac Surg. 2010;37:819–823.

Incidence and Risk factors

Canine transmissible venereal tumor (TVT), also known as transmissible venereal sarcoma and Sticker’s sarcoma, is a naturally occurring, horizontally transmitted infectious histiocytic tumor of dogs usually spread by coitus, but it may also be spread by licking, biting, and sniffing tumor-affected areas.^1-5 It has been observed occasionally in other canids, such as foxes, coyotes, and jackals.^1,2 It has also been known as infectious sarcoma, venereal granuloma, canine condyloma, transmissible sarcoma, and transmissible lymphosarcoma.^6,7

Although TVT has a worldwide distribution, its prevalence is highest in tropical and subtropical areas, particularly in the southern United States, Central and South America, southeast Europe, Ireland, Japan, China, the Far East, the Middle East, and parts of Africa.^1,2 In enzootic areas, where breeding is poorly controlled and there are high numbers of free-roaming sexually active dogs, TVT is the most common canine tumor.^1-3,8 In North America, prevalence of TVT is correlated with increased rainfall and mean annual temperature.⁹ Occasional cases occur in regions otherwise free of TVT following travel to endemic areas as a result of tourism.¹⁰ Pets travelling abroad can be exposed to TVT and carry it back home to nonendemic areas; therefore veterinarians may act as the first line of defense against the introduction of TVT as an emerging disease in nonendemic areas.

Because TVT is primarily spread by coitus, free-roaming, sexually intact mature dogs are at greatest risk.² Dogs of any breed, age, or sex are susceptible.^1,2,6 No heritable breed-related predisposition has been found.^2,6 In endemic areas, although dogs over 1 year of age are at high risk, TVT is most common in dogs 2 to 5 years of age.² The physical exertions associated with coitus in the dog with extensive abrasions and bleeding make both sexes susceptible to injury to the genital mucosa, which facilitates the exfoliation and implantation of tumor cells.^2,6 Transmission can occur efficiently in either direction between the dog and the bitch. The most common sites of involvement are the external genitalia, but other sites that can be affected through licking or sniffing include the nasal and oral cavities, subcutaneous tissues, and the eyes.^1-4,6,11-14 Spontaneous regressions occur and have been associated with immune responses against the tumor. Hence immunosuppression from any cause may be a risk factor for the development and maintenance of TVT and may predispose to widespread dissemination. When spontaneous regressions occurs, it usually starts within 3 months after implantation but rarely after 9 months of tumor.⁶

TVT is a transmissible allograft spread directly from dog to dog across major histocompatibility complex (MHC) barriers through transplantation of viable tumor cells on damaged mucosa through coitus or sniffing and licking.¹⁵ TVT and Tasmanian devil facial tumor disease (DFTD) are the only known naturally occurring clonally transmissible cancers that behave like an infectious parasitic neoplastic tissue graft.¹⁶ These cancers have overcome the limitations of existing within the single host, which gave rise to the tumors by gaining the ability to spread between individuals and thus survive long after the original hosts have died.

Pathology and Natural Behavior

TVT was initially recognized in 1876 and was utilized for the first successful experimental transmission of a tumor.⁶ A number of characteristics of TVT suggest that the tumor originated in inbred wolves or dogs about 10,000 to 15,000 years ago around the time that the dog was domesticated and subsequently the tumor has been spread worldwide.¹⁷ TVT has evolved into a transmissible parasite representing the oldest known colony of cloned somatic mammalian cells in continuous propagation.

Tumor growth generally appears on the external genitalia or nasal or oral mucosa within 2 to 6 months of mating and can either grow slowly and unpredictably for years or grow invasively and eventually become malignant and metastasize.^1,2,6 Extragenital lesions can occur both alone (in isolation) and in association with genital lesions; however, it has been suggested that in most cases neoplastic foci can be detected on the genitalia.

TVT usually remains localized, but metastasis occurs in up to 5% to 17% of cases to draining regional lymph nodes (i.e., inguinal, iliac, tonsils), subcutaneous tissue, skin, eyes, oral mucosa, liver, spleen, peritoneum, hypophysis, brain, and bone marrow.^2,11,18-20 Because TVT is also transmitted by licking, sniffing, and biting, many cases of reported metastases may instead actually be spread of the growth by mechanical extension or autotransplantation or heterotransplantation. Spontaneous regression can occur within 3 to 6 months of implantation, but the chance of self-regression is remote if the tumor is present for over 9 months.²

TVT is commonly described as a round (or discrete) cell tumor and suggested to be of histiocytic origin.⁶ This is supported by immunohistochemical (IHC) expression of vimentin, lysozyme, alpha-1-antitrypsin (AAT), and macrophage-specific ACM1, as well as negative IHC staining specific for other cell types.^4,6,21,22 Immunohistochemistry has been helpful in confirming metastatic TVT in various anatomic locations.^18-20 Furthermore, there have been reports describing TVT cells with intracellular Leishmania organisms also suggesting a histiocytic origin.^14,23

Cytogenetic and genetic analyses have provided robust evidence of clonality. Whereas normal canine cell chromosomes consist of 76 acrocentric autosomes plus submetacentric X and Y sex chromosomes, TVT cells have a vastly rearranged karyotype consisting of 57 to 59 chromosomes, including 15 to 17 submetacentric chromosomes as a result of multiple centric fusions.^4,17 However, the total number of chromosome arms in TVT is grossly comparable to the normal dog, so it appears the karyotypic rearrangement is not associated with significant change in DNA content.^15,17 Although TVT cells are aneuploid, they exhibit remarkably stable and similar karyotypes in samples obtained from widely separate geographic regions (i.e., different continents).¹⁵ Likewise, molecular genetic studies of globally distributed TVT tumors provide evidence of a monophyletic origin, which has diverged into two subclades.^15,24

In addition, TVT cells all share an insertion of a long interspersed nuclear element (LINE-1) upstream of the c-myc oncogene that is not found in normal dog genomes.^25-29 This insertion has the potential to disrupt transcriptional regulation of downstream genes, possibly initiating oncogenic activity, and may have been causally involved in the origin of the tumor.³⁰ This unique rearranged LINE-c-myc gene sequence has been used with polymerase chain reaction (PCR) as a diagnostic marker of TVT to confirm diagnosis.^31,32 TVT cells have also demonstrated point mutations in the tumor suppressor gene p53, which is responsible for protecting the integrity of the DNA.^29,33,34 Mutations of such a key regulator of the cell cycle, apoptosis, and senescence may be another factor in the oncogenesis of TVT.

TVT is an immunogenic tumor and the immunologic response of the host appears to play a critical role in determining the natural behavior of the disease. The course of disease is divided into a progressive phase (P) in which the tumor grows for 3 to 6 months, then a short stationary phase (S), which is followed by a regressive phase (R) in most dogs, unless the dog is elderly, in poor general condition, or immunologically compromised.^6,8,35-44

Initially, in the P phase, the tumor downregulates its MHC class I β2-microglobulin and class II expression, which allows it to evade the host’s histocompatibility barrier, particularly T-cell cytotoxicity.⁴⁵ Some cell-surface MHC class I expression remains, likely to prevent recognition and killing by natural killer (NK) cells. This immunoevasion is partly due to the high concentration of tumor-secreted transforming growth factor-β1 (TGF-β1), which inhibits tumor MHC antigen expression and NK cell activity.⁴⁰ TVT also targets and damages dendritic cells (DCs).⁴⁵ It has been suggested that TVT has evolved under survival pressures to escape host immunosurveillance.⁴⁶

Tumor-infiltrating lymphocytes (TILs) produce IFNγ but fail to promote tumor MHC expression due to inhibition of IFNγ effects by tumor-derived TGF-β1, which also suppresses the cytotoxicity of the NK cells that migrate to the tumor site because of low tumor-antigen expression.^36,39,40 However, late in the P phase, TILs produce high concentrations of the proinflammatory cytokine IL-6, which acts synergistically with host-derived IFNγ to antagonize the immunoinhibitory activity of TGF-β1 and results in MHC expression in up to 40% of tumor cells and restores NK cytotoxicity.^37,47 A critical threshold level of IL-6 secreted by TILs has to be reached to trigger TVT into R phase.^40,47 Therefore, after progressive growth for 3 to 4 months, the tumor spontaneously regresses with upregulation of MHC antigen expression possibly under epigenetic control.⁴⁶

In addition to cell-mediated immunity, TVT also elicits a humoral immune response demonstrable by antibodies against TVT antigens.^35,48 Experimentally, immunocompromised dogs do not demonstrate regression but rather continued progression of TVT and widespread metastatic disease.⁶ Conversely, dogs recovered from TVT have serum-transferable immunity to reinfection and puppies born to bitches exposed to TVT are less susceptible to the disease.⁴⁹ In addition to the host immune response, during TVT regression stromal cells and extracellular matrix (ECM) react comparably to wound repair with collapse of the tumor parenchyma and replacement by fibrous stroma.⁴³

History and Clinical Signs

The archetypical TVT patient is a sexually intact young adult dog either living in or having travelled to an area endemic for TVT, with a history of contact (coitus, sniffing, licking, or biting) with dogs of similar signalment.^1,2,6,7 The primary lesions are usually on the external genitalia. In the male, the tumor is usually located on the caudal part of the penis, requiring caudal retraction of the penile sheath for visualization (Figure 33-6).^2,6 Occasionally, it is on the prepuce. In the bitch, the tumor is usually in the posterior vagina or vestibule.^2,6 Tumors appear initially as small 1 to 3 mm hyperemic papules that progress by fusing together into nodular, papillary, multilobulated cauliflower-like or pedunculated proliferations up to 10 to 15 cm in diameter. The mass is firm but friable, with an ulcerated inflamed surface. The tumor often oozes a serosanguineous or hemorrhagic fluid. Examples of extragenital sites are illustrated in Figure 33-7.

Clinical signs vary according to the location of the lesions. Genital lesions often manifest with chronic signs of discomfort or hemorrhagic discharge from the penile sheath or vulva for weeks to months prior to diagnosis, which can result in anemia.^2,6,7 Lesions can predispose to ascending bacterial urinary tract infections but rarely interfere with micturition.⁵⁰ Extragenital lesions cause a variety of signs, depending on anatomic location, such as sneezing, epistaxis, epiphora, halitosis, tooth loss, exophthalmos, skin masses, facial deformation, and regional lymph node enlargement.

Diagnostic Techniques and Work-Up

A presumptive diagnosis of TVT can be obtained based on history (including travel), signalment, clinical signs, and physical findings in dogs with the classic presentation. Definitive diagnosis is based on cytologic examination of cells obtained by swabs, FNAs, or imprints of the tumors or histologic examination of a biopsy from the mass. TVT is described as a discrete (or round) cell tumor. TVT has a characteristic morphologic appearance on cytopathology and is often diagnosed without need for histopathology (see Figure 7-37). Exfoliative cytology demonstrates uniform discrete round to polyhedral-shaped cells with moderately abundant pale blue cytoplasm and an eccentrically located nucleus, with occasional binucleation and mitotic figures.^4,6 Single or multiple nucleoli are often observed, surrounded by clumped chromatin. The most characteristic feature is the presence of numerous discrete clear cytoplasmic vacuoles. In R phase, TVTs contain a higher number of infiltrating lymphocytes. Other round cell tumors, including lymphomas, mast cell tumors, plasma cell tumors, histiocytomas, and amelanotic melanomas, are important differential diagnoses but are generally not confused with TVT on cytopathology.

Histopathology of TVT reveals compact masses of round or polyhedral cells with slightly granular, vacuolated, eosinophilic cytoplasm.^4,6 The neoplastic cells are arranged in a diffuse pattern and supported by a thin trabecula of fibrovascular tissue. Regressing tumors are infiltrated by lymphocytes, plasma cells, and macrophages.⁶ For atypical TVTs, if there is doubt about the diagnosis, specific molecular techniques can be utilized (e.g., in situ PCR of the rearranged LINE-c-myc gene sequence).³¹

The incidence of metastatic spread of TVT has been reported as less than 15%. However, in most cases of TVT, tumor staging is not performed. Therefore the metastatic rate might be higher. Regional lymph nodes should always be evaluated for metastasis by palpation and cytopathology. A thorough physical examination is essential to rule out other possible sites of involvement (i.e., skin, subcutis, nasal and oral cavities, the eye, the orbit). Diagnostic imaging is usually not required except with invasive TVT of the nasal cavity, orbit, or unusual locations. However, abdominal ultrasound may be used to image regional lymph nodes. CBC, serum biochemistry profile, and urinalysis do not reveal specific changes. Dogs bearing a large tumor burden of TVT have been associated with a paraneoplastic erythrocytosis that may require temporary symptomatic therapy.⁶

Therapy

TVTs will respond to many forms of therapy; however, chemotherapy is the most effective. Single-agent vincristine (0.5 to 0.7 mg/m² intravenous [IV], once weekly for 3 to 6 treatments) obtains a complete and durable response in 90% to 95% of treated dogs.* Other single-agent and combination multiagent protocols employing cyclophosphamide, vinblastine, methotrexate, and prednisolone have not demonstrated superiority to vincristine alone.^52,53,56 Resistant cases can be treated with DOX (25 to 30 mg/m² IV, every 21 days for 3 treatments).¹

RT has demonstrated efficacy against TVT. In a study using orthovoltage radiation at 1000 to 3000 cGy, all 18 dogs treated responded with a complete and durable response.⁵⁷ Seven dogs were cured with a single coarse fraction of 1000 cGy. The other 11 dogs required 2 or 3 fractions to achieve complete response. Three of the 18 dogs were presented after recurrence following chemotherapy. Another study using megavoltage radiation from a Cobalt-60 unit reported all 15 dogs achieved complete and durable responses with 3 fractions administered over 1 week, for an average dose of 1500 cGy.¹¹

Four of the 15 dogs had been resistant to vincristine. Therefore RT can be considered an effective treatment for TVT, particularly for lesions showing resistance to chemotherapy or located in sanctuary sites from chemotherapy (i.e., brain, testicle, eye).

Surgery can be an effective treatment for small localized TVT; however, surgery has an overall recurrence rate of 30% to 75%.^58,59 Marginal surgical excision is not effective, and it can be difficult to obtain wide surgical margins in the areas in which TVT typically appears.^58,59 In addition, tumor transplantation into the surgical wound by contamination from instruments or gloves may also cause postoperative tumor recurrence.

Other therapies described in spontaneous and experimentally induced cases include biologic-response modifiers, piroxicam, cryosurgery, radiofrequency ablation, laser ablation, and electrochemotherapy.^60-64

Reduction of the incidence of TVT is possible by having dog owners and breeders carefully examine all males and females before mating to avoid breeding from affected animals.² In addition, stray dogs can act as a TVT reservoir; therefore the mingling of breeding dogs with strays should be prevented. In some areas, the control of ownerless, free-roaming dogs can drastically reduce the incidence of TVT. TVT can enter the wild canid population through physical contact (licking, biting, or mating), and it is not known whether TVT could pose a threat to endangered wild canids.⁶⁵

Prognosis

In most cases, TVT remains localized and rarely becomes disseminated in an immunocompetent host. In fact, a number of dogs will have their TVT spontaneously regress. For those dogs requiring treatment with vincristine or radiation, the prognosis for complete and durable clinical remission is excellent. Therefore the overall prognosis of canine TVT is generally very good to excellent. In stark contrast, the other naturally occurring transmissible tumor allograft, the Tasmanian DFTD, is highly virulent and kills most affected animals within 6 months by obstructing their ability to feed or breathe. It is speculated that the difference in virulence between the two allografts is due to the loss of MHC diversity in the Tasmanian devils, and perhaps one reason for MHC diversity in vertebrates is to ensure that cancer is not communicable between hosts like an infectious disease.^15,17,46